ArticleThe Journal of biological chemistry2015
Microseconds simulations reveal a new sodium-binding site and the mechanism of sodium-coupled substrate uptake by LeuT.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Molecular mechanisms of NaBiophysical journal · 2024Article
- Sodium/Iodide Symporter Metastable Intermediates Provide Insights into Conformational Transition between Principal Thermodynamic States.The journal of physical chemistry. B · 2023Article
- Structure-based virtual screening and molecular dynamics of potential inhibitors targeting sodium-bile acid co-transporter of carcinogenic liver fluke Clonorchis sinensis.PLoS neglected tropical diseases · 2022Article
- Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions.Cells · 2022Article
- Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations.Frontiers in cellular neuroscience · 2021Article
- Computational Dissection of Membrane Transport at a Microscopic Level.Trends in biochemical sciences · 2020Review
- Locking Two Rigid-body Bundles in an Outward-Facing Conformation: The Ion-coupling Mechanism in a LeuT-fold Transporter.Scientific reports · 2019Article
- Serotonin transport in the 21st century.The Journal of general physiology · 2019Review
- Monoamine transporters: structure, intrinsic dynamics and allosteric regulation.Nature structural & molecular biology · 2019Review
- NaPhysical chemistry chemical physics : PCCP · 2019Article
- Quantitative Assessment of the Energetics of Dopamine Translocation by Human Dopamine Transporter.The journal of physical chemistry. B · 2018Article
- How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties.BMC biology · 2018Article
- Modification of a Putative Third Sodium Site in the Glycine Transporter GlyT2 Influences the Chloride Dependence of Substrate Transport.Frontiers in molecular neuroscience · 2018Article
- Allosteric modulation of human dopamine transporter activity under conditions promoting its dimerization.The Journal of biological chemistry · 2017Article
- Effect of Dimerization on the Dynamics of Neurotransmitter:Sodium Symporters.The journal of physical chemistry. B · 2017Article
- The Environment Shapes the Inner Vestibule of LeuT.PLoS computational biology · 2016Article
- Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu290.The Journal of biological chemistry · 2016Article
- Na+ coordination at the Na2 site of the Na+/I- symporter.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- A conserved leucine occupies the empty substrate site of LeuT in the Na(+)-free return state.Nature communications · 2016Article
- Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog.The Journal of biological chemistry · 2016Article
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3 authors.
Funding
Abstract
The bacterial sodium-coupled leucine/alanine transporter LeuT is broadly used as a model system for studying the transport mechanism of neurotransmitters because of its structural and functional homology to mammalian transporters such as serotonin, dopamine, or norepinephrine transporters, and because of the resolution of its structure in different states. Although the binding sites (S1 for substrate, and Na1 and Na2 for two co-transported sodium ions) have been resolved, we still lack a mechanistic understanding of coupled Na(+)- and substrate-binding events. We present here results from extensive (>20 μs) unbiased molecular dynamics simulations generated using the latest computing technology. Simulations show that sodium binds initially the Na1 site, but not Na2, and, consistently, sodium unbinding/escape to the extracellular (EC) region first takes place at Na2, succeeded by Na1. Na2 diffusion back to the EC medium requires prior dissociation of substrate from S1. Significantly, Na(+) binding (and unbinding) consistently involves a transient binding to a newly discovered site, Na1″, near S1, as an intermediate state. A robust sequence of substrate uptake events coupled to sodium bindings and translocations between those sites assisted by hydration emerges from the simulations: (i) bindings of a first Na(+) to Na1″, translocation to Na1, a second Na(+) to vacated Na1″ and then to Na2, and substrate to S1; (ii) rotation of Phe(253) aromatic group to seclude the substrate from the EC region; and (iii) concerted tilting of TM1b and TM6a toward TM3 and TM8 to close the EC vestibule.
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